The present invention relates generally to methods for treating infertility.
Infertility effects an estimated 1 in 5 couples in the United States. The Merck Manual, p. 1768 (16th Ed. 1992). About 40 percent of infertilities are due to male deficiency, 40-50 percent to female anatomic or hormonal defects, and the remainder to indeterminate factors. 17 McGraw-Hill Encyclopedia of Science and Technology, p. 417 (6th Ed. 1987).
Infertility refers to the inability to conceive during the course of normal sexual activity. However, a couple is generally not regarded as infertile until they have failed to conceive after one year of unprotected intercourse. Diagnosis and treatment of infertility requires a thorough assessment of both partners. The Merck Manual, p. 1768 (16th Ed. 1992).
The major factors leading to female infertility include: ovulatory dysfunction; abnormal tubular function; and cervical factors. In addition to these three factors, other undetermined factors also cause infertility. An undefined factor may be a compromised ability of the egg/embryo to produce a functioning fertilization envelope or withstand toxic effects of oxidants.
Immediately following fertilization in metazoans, including mammals, the external layer of the egg is rapidly modified to an effective barrier ("fertilization envelope"). The barrier protects the early embryo and prevents further entry of spermatozoa.
Shapiro, The Control of Oxidant Stress at Fertilization, Science, Vol. 252, pp. 533-36 (1991) discusses the production of a fertilization envelope in a sea urchin egg. Due to the large production of eggs, the sea urchin provides an excellent experimental system for studying molecular mechanisms of fertilization. In the sea urchin egg, a strong oxidant, probably hydrogen peroxide, is produced at or near the plasma membrane. An enzyme ("ovoperoxidase" in the invertebrate egg) uses the oxidant to initiate a cross-linking of proteins external to the egg surface. The cross-linking ultimately forms a protective fertilization envelope. The fertilization envelope persists for times that vary among species.
An oxidant, such as hydrogen peroxide, can cause significant damage if it enters the egg (either before or after fertilization) in significant amounts. The egg/embryo has biochemical mechanisms for handling oxidant which does defuse into it. In some animals, a family of modified amino acids ("ovothiols") consume hydrogen peroxide and are thereby oxidized to a disulfide. A reduced glutathione then reduces the ovothiol-disulfide to a thiolate. The ovothiol is then free to consume more oxidant.
The male deficiency most commonly responsible for infertility is a deficiency of sperm production in quantity or quality. 17 McGraw-Hill Encyclopedia, supra, at 417. The quantity and quality of sperm production depends, among other things, on the protection of the sperm cell membrane during and after ejaculation.
Similar to the potential peroxidation of the egg/embryo, oxidants within the male reproductive system can cause significant damage if they enter the sperm. Oxidants that diffuse into the sperm could be toxic. Thus, like the egg's biochemical mechanism for handling oxidants, semen in the male reproductive tract also has an effective defense mechanism. Glutathione plays a key role in this defense mechanism.
Glutathione plays a vital role in the protection of the sperm as well as the egg/embryo. Glutathione in its reduced state facilitates the consumption of oxidants which can cause significant damage if they enter the sperm or egg before or after fertilization.
The important role of glutathione will be compromised if the intracellular level of glutathione or the partitioning between the reduced and oxidized forms is abnormal. Such abnormality could ultimately be responsible for infertility, due to the compromised ability of the egg/embryo and sperm to produce respectively a functioning envelope and membrane or withstand toxic effects of oxidants.
Further, a compromised level of glutathione in the egg or uterine wall may also effect implantation of the fertilized egg. An inability to implant the fertilized egg could also cause infertility.